Viral respiratory infections are a frequent cause of increased wheezing in patients with asthma. Although the consequences of viral infections on airway function are often severe and prolonged, the precise mechanisms by which these respiratory illnesses increase asthma have yet to be fully established. The overall objective of this proposal is to establish the mechanisms by which viral respiratory infections result in biologic and physiologic alterations to cause asthma. From observations in humans experimentally infected with rhinovirus, and in laboratory animals infected with respiratory viral pathogens, we have evidence that the regulation of airway inflammation is a major factor in the development of virus-induced asthma. Based upon these observations, it is our overall hypothesis that a major mechanism for viral respiratory infection-induced bronchial hyperresponsiveness and asthma is an enhanced activity of those cells and factors that participate in airway inflammation. To extend our previous observations and further examine our experimental hypothesis, we propose an integrated series of experiments in both humans and rodent models. Specifically, we will use bronchoscopy, segmental antigen challenge, lavage and biopsy in rhinovirus 16 infected humans to determine the ability of virus to activate airway cells to secret pro-inflammatory cytokines and amplify bronchial inflammation by increasing local expression of adhesion molecules, promoting greater inflammatory cell recruitment, and potentiating inflammatory cell function. These observations will be extended to evaluate the effect of pro-inflammatory cytokine secretion by respiratory virus activated mononuclear cells which in turn promote the secretion of cytokine generation by allergen activated T-cell clones. In parainfluenza (Sendai virus) infected rats, we will examine the ability of virus to alter phospholipid metabolism to favor an increased production of eicosanoids that subsequently augment airway tone, obstruction and hyperresponsiveness. In the same model, we will determine whether viral bronchiolitis induces accentuated cytokine gene expression that results in altered bronchiolar growth and in airway inflammatory cell number and function to cause persistent airway obstruction and hyperresponsiveness. In the parainfluenza-3 infected guinea pig, we will determine how infection of tracheal epithelial cells modifies their function and thus regulation of mediator release and airway responsiveness. The proposed experiments in humans and animals will provide complementary and collaborative new mechanistic information on the biologic, physiologic, and molecular interactions that occur between respiratory viruses, the immune system, and the airways to result in bronchial hyperresponsiveness and asthma.